Systemic Lupus Erythematosus (SLE), the prototypic systemic autoimmune disease, is characterized by myriad immune abnormalities including excessive autoantibody production, activation of the complement system, lymphocyte dysfunction, and lymphopenia. Upon activation of the complement system, proteolytic cleavage of C3 and C4 results ultimately in the generation of C3d and C4d fragments that contain the highly reactive thioester moiety and can bind covalently to the surfaces of pathogens, cells, or immune complexes. The present inventors have recently reported that significant levels of C4d are present specifically on the surfaces of erythrocytes, reticulocytes, platelets, and lymphocytes of patients with SLE. A recent multicenter study validated cell-bound complement activation products (CB-CAPs) as diagnostic biomarkers for lupus and additional reports have demonstrated their significant potential as biomarkers of lupus disease activity and stratification.
In addition to their roles as lupus biomarkers, CB-CAPs have been shown to confer functional abnormalities to circulating cells such as erythrocytes and T lymphocytes, suggesting a role in lupus pathogenesis. Elucidation of the cellular and molecular events whereby CB-CAPs are generated may lead to identification of potential therapeutic targets either by preventing, disrupting, or neutralizing the downstream effects of CB-CAP generation. One of the most intriguing potential links between CB-CAPs and lupus pathogenesis is the longstanding yet poorly understood observation that patients with SLE harbor circulating anti-lymphocyte antibodies.
Anti-Lymphocyte antibodies (ALA) in patients with SLE, particularly those specific for T cells, were discovered in the 1970's. Since then, numerous efforts have been made to characterize these ALA. However, their role in disease pathogenesis has remained uncertain. Two primary types of anti-T cell antibodies in SLE have been described previously. First, cold reactive IgM antibodies, which bind optimally to T cells at 4° C., have been reported as common in patients with SLE. However, the in vivo significance of these antibodies is unclear because of the thermal difference between in vitro assays and in vivo pathogenic molecular and cellular mechanisms. Second, warm-reactive IgG anti-T cell antibodies in lupus have been reported. These antibodies have been shown to have heterogeneous specificities against a variety of T cell surface molecules including CD3, CD4, CD45, and IL-2R.
Two distinct roles for these IgM versus IgG anti-T cell antibodies in lupus pathogenesis have been suggested, both of which involve destruction of the cellular targets. IgM is 500-fold more effective in activation of the classical complement pathway, suggesting possible lytic attack of T cells. However, if binding of these cold-reactive IgM molecules only occurs at low temperatures, this would eliminate this possibility in vivo. In addition, the presence of IgM anti-T cell antibodies has not been shown to correlate with lymphopenia in SLE. IgG are less potent complement activators, however their warm-reactivity makes such an in vivo mechanism at least feasible. Other potential roles for anti-T cell IgG have been suggested including antibody dependent cellular cytotoxicity (ADCC) and modulation of T cell signaling and gene expression.
Some reports have suggested that T lymphocyte dysfunction in lupus might be triggered by circulating IgM and IgG anti-T cell autoantibodies rather than due to intrinsic defects although the two possibilities are not mutually exclusive. Collectively, these prior reports have suggested that anti-T cell antibodies are present in some patients with SLE and elucidation of their potential role(s) in disease pathogenesis should consider isotype, thermal amplitude of binding and cytotoxicity, and antigenic specificity.